As of yet, no approved drug exists for treating the cause of Alzheimer's Disease (AD). Typically, deposits of the so-called beta amyloid peptides (Aβ) in plaques are found in the brains of AD patients post mortem. This is the reason why, for quite some time, various forms of the Abeta (also referred to as Aβ), such as fibrils, have been considered to be responsible for the development and progression of Alzheimer's disease.
In recent years, in particular the small, freely diffusable Aβ oligomers have been regarded as the primary causative factor in the development and progression of Alzheimer's disease.
Aβ monomers are continuously created in our body and are presumably not toxic per se.
There is speculation as to whether Aβ monomers agglomerate to form Aβ oligomers randomly as a function of the concentration thereof, which ultimately results from formation and decomposition rates in the body, and thus, with increasing age, are increasingly likely to do so spontaneously. Once Aβ oligomers have developed, it is possible that they then multiply by way of a prion-like mechanism and ultimately lead to disease.
Based on these considerations, it should be the goal of a causative treatment to completely destroy toxic Aβ oligomers and/or prevent the prion-like multiplication thereof.
However, no drug for the treatment for Alzheimer's disease is available which acts to combat the cause. Drugs that are used according to the prior art are able to alleviate some symptoms at best, but cannot slow, let alone stop, the progression of the disease.
A number of substances exist that, in animal experiments, are able to achieve some success in terms of prevention (not necessarily the treatment) of Alzheimer's disease.
An important distinction between prevention and treatment lies in the following consideration: So as to prevent the formation of initial Aβ oligomers, Aβ ligands having low affinity and effectiveness may suffice. Since the formation of an Aβ oligomer from multiple Aβ monomers is a reaction of a very high order, it is dependent to a high degree on the Aβ monomer concentration. Even a small reduction in the active Aβ monomer concentration can thus prevent the initial Aβ oligomers from forming. This is the situation with prevention. However, if Aβ oligomers have already been created, these are able to multiply in a prion-like manner, which is not a reaction of a high order and consequently almost independent of the Aβ monomer concentration. This is the situation with treatment. As a result, if Aβ oligomers have already been created, the goal of a treatment must be to address these with substances that have the highest possible affinity to Aβ oligomers. The corresponding dissociation constant would have to be in the pM range, or even lower.
At present, several substances exist that reduce the concentration of Aβ monomers in a wide variety of ways, for example by way of gamma secretase modulators, Aβ-binding ligands, and so forth. This appears to suffice to provide successful preventive action in animal experiments, in which animals are usually already undergoing treatment before the disease fully manifests itself.
In clinical human trials (phases II and III), where only individuals that have been clearly diagnosed with Alzheimer's disease are allowed to be treated, however, all these substances have failed so far, possibly because, in these instances, which is to say prior to the onset of the disease, a small or moderate decrease in the Aβ monomer concentration is not sufficient to prevent the development of increasingly greater amounts of Aβ oligomers.
Furthermore, it is not currently possible to diagnose Alzheimer's disease reliably before symptoms appear. Today, Alzheimer's disease is primarily detected through neuropsychological tests on persons already suffering from symptoms of dementia. Furthermore, other diseases (traumas) can be excluded by way of various examination methods.
However, it is known that Aβ oligomers, and subsequently plaque, develop in the brain of patients up to 20 years prior to the appearance of symptoms and cause irreversible damage. Molecular probes, which are intravenously injected into the patient and bind to Aβ oligomers and plaque after passing the blood-brain barrier, can be rendered visible by way of imaging methods, and thus allow an earlier diagnosis of AD.
A D-enantiomeric peptide by the name “D3” is known from EP 1 379 546 B1. The peptide was identified by way of a mirror image phage display selection against predominantly monomeric Aβ(1-42), with the goal of stabilizing the same with the bond and preventing conversion into toxic Aβ aggregates. Based on current knowledge, D3 preferably converts the particularly toxic Aβ oligomers into non-toxic, non-amyloidogenic and ThT negative amorphous aggregates. In animal models, even oral administration of D3 with drinking water results in treated transgenic AD mice containing considerably less plaque and having significantly improved cognitive abilities.
Further peptides derived from D3 are known from the publication WO 2014/041115 A2.
The disadvantage is that the existing Aβ oligomer-binding substances have insufficient affinity to prevent the multiplication of Aβ oligomers.
A disadvantage is that, so far, there are no probes for in vivo imaging methods which bind with high affinity specifically to Aβ oligomers and render these visible. Since Aβ oligomers play such an important and early role in the history of the disease, precisely this would be desirable.